Alpha-acetophenylcinnamonitriles and derivatives thereof



United States Patent U 23m ns a-ACETOPl-EEN YLCINNAMiENi l REES AND DERWATEVES THEREOF Kurt Rorig, Chicago, 111., assignor to G. D. Searle & Co., Chicago, 111., a corporation of lllinois No Drawing. Application Jnne 36, 1952, Serial No. 296,439

9 Claims. or. 26 3465) The present invention relates to a new group of organic nitriles and their preparation and, more particularly, to the condense ion of an aceto-a.-tolunitrile with benzaldehydes and the products produced by this reaction. The reaction can be represented by structural formulas as follows:

OHS-GO CN In these formulas Ar is either a phenyl or a substituted phenyl radical. Since the aceto-a-tolunitrile molecule contains an active methylene as well as an active methyl group, attack of the aldehyde group occurs on both of these places. It has been found that the methylene group between the nitrile radical and the benzene ring is more active than the methyl group adjacent to the carbonyl radical and therefore the reaction rnixture contains a larger quantity of the a-acetcphenylcinnamonitrile than of the cyanomethylchalcone. The two isomers can be separated by fractional crystallization.

in the above structural formulas Ar represents a phenyl radical which may be substituted by such groups as lower alkyl, hydroxy, lower alkony, halogen, nitro, amino, lower dialkylarnino and cyano radicals.

The products otthis condensation reaction are valuable medicinal agents especially because of their antagonism of endocrine functions, particularly of desoxycorticosterone-like adrenocorticoid activity. They also are useful as intermediates in organic synthesis. Thus hydrolysis of the nitriles yields the free acids which can then be esterified to form medicinally useful lower dialkylarninoalkyl esters.

The examples below i ustrate in detail some of the compounds which con? ise this invention and methods for their production. Ho yever this invention is not to be construed as limited thereby in spirit or in scope. In each of these examples temperatures are given uncorrected in degrees Centigrade (C.), pressures in millimeters (mm.) of mercury and relative amounts of materials in parts by weight.

EXAMPLE 1 a- (4-acet0phenyl cinnamoizitrile and some 4-cyanornethylchalcone in which the former predominates. These compounds have the structural EXAMPLE 2 4-ir0propyl-c4 (3-acet0phenyl) cinnamonitrile 'lin solution of 159 parts of 3-acetotolunitrile and t f cumaldchyde in 1600 parts of methanol is l 5 parts of sodium methoxide. On cooling there precipitates a mixture or" 4-isopropyl-a-(3-acetophenyl)cinnamonitrile and some 3-cyanornethyl4-isopropylchalccne. The predominating isomer can be obtained in a greater degree of purity by successive recrystallizations from ethanol and dioxane. ucts have the structural formulas NC-CHz The prod- EXAMPLE 3 4-mezhoxy-e-(3-acerophenyl) cz'mznmoizitrile I als 92-98 C. These compounds have the structural formulas I CHaCO COOH=CHOCH3 NC-$112 Purification of the predominant isomer by recrystallization from ethanol yields crystals melting at about 102.5-

1035" C. EXAMPLE 4- 3-meth0xy-ri- (4-zrcezophenyl) cinnamonitrile A solution of 136 parts of 3-methoxybenzaldehyde and O 15 parts of 4-acetotolunitrile in 800 parts of methanol is heated to boiling and treated with 10 parts of sodium methoxide. There is an immediate formation of a dark color and upon cooling a pale yellow flufify product precipitates which melts at about 110-116" C. in this mixture of 3-methoxy-u-(4-acetophenyl)cinnamonitrile and some 4'-cyanomethyl-3-methoxychalcone the former isomer predominates. Two recrystallizatiorls from ethanol yield crystals melting at about 124126 C. containing the predominant isomer in relatively pure form.

EXAMPLE I 5 4-meth0xy-ot- (4-acet0phenyl) cinnamonitrile EXAMPLE 6 3 -meIh0xy-4-hydr0xy-a- (4-acet0phenyl cinnamonitril e A solution of 159 parts of 4-acetotolunitrile and 152 parts of vanillin in 1000 parts of boiling methanol is treated with parts of sodium methoxide. Upon standing at room temperature a mixture of 3-methoxy-4-hydroxy-ot-(4-acetophenyl)cinnamonitrile and some 4-cyanomethyl-3-methoxy 4 hydroxychalcone precipitates. The compounds have the structural formulas OCH;

OCHa

. ris ue-Q4: 0-on=on The predominating isomer can be obtained by recrystalli-' zation from ethanol. 7

EXAMPLE 7 4-chl0r0-u- (4-acet0phenyl) cinnamonitril e A boiling solution of 80 parts'of 4-acetotolunitrile and 70 parts. of -chlorobenzaldehyde in 1000 parts of methanol is treated with 5 parts of sodium methoxide and per- C mitted to stand at room temperature for 45 minutes. The resulting precipitate of the mixture of 4-chloro-a- (4 acetophenyl)cinnamonitrile and some 4-cyanomethyl-4- chlorochalcone melts at about 133138 C. The products 7 have the structural formulas on CHaC o--o=on- 411 V V o-om-Qc OCH=CHC1 On recrystallization from ethanol white crystals are obtained, melting at about 136-143 C.

EXAMPLE 8 Z-bEomq e (4-tz cet0 phenyl) cinnamonirrile A solution of 63.6 parts of 4-acetotolunitrile and 74 parts of Z-bromobenzaldehyde in 520 parts of methanol is heated to about C. and treated with 5 parts of sodium methoxide. Within two minutes long slender needles of an ivory colored solid are formed which are collected on a filter. They melt at about 137'142 C.

and contain 2 bromo-a-(4-acetophenyl)cinnamonitrile Car and some 4-cyanomethyl-Z-bromochalcone. ucts have the structural formulas I CN Br NC-Om-Q-Q o-on=on Upon recrystallization from ethanol white needles of the predominant isomer are obtainedin relatively pure form, melting at about l46-147 C.

7 EXAMPLE 9 V 2 -amin0- z- 3-acet0phenyl cinnamonitrile A solution of 159 parts of 3-aeetotolunitrile and 121 parts of anthrauilaldehyde in 1000 parts of boiling methanol is treated with 10 parts of sodium methoxide. The solution becomes colored at once and a yellow fiuify precipitate is formed which is collected on a filter. This mixture contains Z-amino a (3 acetophenyl)cinnamonitrile and some 3'-cyanomethyl-2-aminochalcone which have the structural formulas (IJN The prodm4; 112 V NHZ EXAMPLE 1O 4-dimer'hylamino-a-(4-acet0phenyl) cinnamonitrilej A solution of 159 parts of 4-acetotolunitrile and 149 parts of 4-dimethylaminobenzaldehyde in 1600 parts of methanol is treated with 10 parts of sodium methoxide. The resulting yellow product is dried. It melts at about 198-200 C. with softening at 190 C. and-consists of 4-dimethylamino a (4-acetophenyl)cinnamonitrile and some 4-cyanomethyl-4-dimethylaminochalcone. Upon repeated recrystallization from dioxane the predominant isomer is obtained in relatively pure form, melting at about 200-201 C. The predominant isomer has the structural formula EXAMPLE 1 1 4-cyan0-a- (3-acet0phenyl) cinnamonitrile A mixture of 159 parts of 3-acetotolunitrile and 131 parts of 4-cyanobenzaldehyde in 1600 parts of methanol is heated to the boiling point and treated with 10 parts of sodium methoxide whereupon the mixture becomes dark brown and a tan solid solidifies within a few minutes. An oil soon deposits on top of this solid. This mixture consists of 4-cyano-a-(3-acetophenyl)cinnamonitrile and some 3'-cyanomethyl-4-cyanochalcone. This semi-solid oil is removed and dried. The decanted liquid soon deposits a well-crystallized substance, melting at about 125 C. Recrystallized from the monocthyl ether of ethylene glycol and washed with alcohol the predominant isomer is obtained asan ivory-colored solid sintering at C. and melting at about 137-14l C. It has the structural formula EXAMPLE 12 4-cyano-a- (4-acet0pkenyl cinnamonitrile I claim: 1. The compounds of the structural formula CHy-CO CN =CH-Ar where in Ar is a member of the class consisting of phenyl,

lower alkylphenyl, methoxyphenyl, hydroxyphenyl, cy-

anophenyl, aminophenyl, di-(lower alkyl)aminophenyl radicals and halophenyl radicals wherein the halogen has an atomic weight greater than 30 and smaller than 100.

2. The compounds of the structural formula 3. The compounds of the structural formula C H 0 O halogen CN D -Q some 4-cyanomethyl-4-cyanochalcone. w

wherein the halogen has an atomic weight greater than 30 and smaller than 100.

4. The compounds of the structural formula C H3 N (lower alkyl) 2 5. 4-dimethylamino-a- 4-acetophenyl) cinnamonitrile. 6. The compounds of the structural formula C 0 (EN CN 7. The compounds of the structural formula wherein Ar is a monocyclic aromatic hydrocarbon radical.

8. The compounds of the structural formula CHa-CO ON 2 f J=CHC5H 9. a- (4-acetophenyl) cinnamonitrile.

References Cited in the file of this patent UNITED STATES PATENTS Moore Jan. 5, 1943 Henecka Mar. 18, 1952 

1. THE COMPOUNDS OF THE STRUCTURAL FORMULA 